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• W2328837568 abstract "Cytomegalovirus (CMV) is a ubiquitous agent recognized as a prominent pathogen in humans. It is a significant cause of morbidity and mortality in the immunocompromised immune deficiency syndrome (AIDS), recipients of organ transplants, burn victims, and patients receiving immunosuppressive therapies (1-12). Cytomegalovirus infection of the gastrointestinal tract has been well described in immunocompromised patients and may be a cause of serious illness (4,5,8,11-17). In an immunocompetent host, the infection is usually asymptomatic. The relatively low pathogenicity of CMV in normal hosts is testimony to the good outcome of the interaction between the host's immune system and the virus (18). Intractable diarrhea of infancy is a serious, potentially life-threatening condition in which the cause of the mucosal injury may not be determined (19). In such cases, diarrhea and malabsorption may persist indefinitely and require total parenteral nutrition for support. Heretofore, CMV has not been recognized as a cause of intractable diarrhea of infancy. We present here such a case in an immunocompetent infant who was successfully treated. CASE REPORT The patient was a 2-month-old boy with no significant medical history. He was born at full term through a normal spontaneous vaginal delivery without complications. His birth weight was 4.03 kg. He was breast fed and thrived until 10 days before admission, when he had watery, green stools without blood or mucous. He had fever for 1 day at the onset of the illness. There was no history of vomiting or upper respiratory tract symptoms. His family history was negative for atopy. His weight was 5.25 kg (50th percentile) and height 58 cm (50th percentile). He did not have jaundice, lymphadenopathy, or organomegaly. His laboratory evaluation showed normal liver function. He was hypoalbuminemic (2.6 g/dl; normal, 3.7-4.8 g/dl). His stools were negative for bacterial pathogens. Campylobacter, Salmonella, Shigella, Aeromonas, and Escherichia coli 0157:H7 were not isolated in specific culture mediums (Campylobacter medium, MacConkey's agar, Hektoen enteric agar, Sheep's blood agar, and MacConkey's agar with sorbitol, respectively). Stools showed no white blood cells, red blood cells, or Charcot-Leyden crystals. Clostridium difficile was not detected in stools. Stool viral cultures were negative in three cell lines (fibroblasts, epithelioid cells, and rhesus monkey kidney cells) which would have isolated adenoviruses, enteroviruses, and herpes viruses. Rotavirus was not detected by a commercial test (Rotaclone; Cambridge Biotech, Westchester, MA, U.S.A.). Stools for ova and parasites were negative in a wet-mount stool examination of stools transported in 10% neutral-buffered formaldehyde and trichrome stain of stools preserved in polyvinyl alcohol. Stools examined for Giardia antigen were negative. Stool electrolytes confirmed secretory diarrhea and α1-antitrypsin was increased in the feces (7.1 mg/g; normal, <3 mg/g) while the patient was receiving nothing orally. Stoll pH was 6, and reducing substances were negative while the patient was receiving oral hydration solution. Homovanillic acid and vanillylmandelic acid in urine were normal, excluding neuroblastoma. Complete blood count was within normal limits (Table 1), showing no atypical lymphocytes or lymphocytosis. There was no eosinophilia. Urinalysis was within normal limits, and urine bacterial culture was negative.TABLE 1: Immune status evaluationDuring a week of complete bowel rest, the patient's stool output remained elevated at 180 ml/kg per day. Total parenteral nutrition was begun on hospital day 5. The patient underwent esophagogastroduodenoscopy and colonoscopy on hospital day 10, but no macroscopic lesions were observed. Biopsy specimens were obtained from second and third portions of the duodenum; antrum; and the right, transverse, and left colon from normal-looking mucosa. Duodenal and colonic mucosal specimens were negative for bacterial enteropathogens in determinations by culture and microscopic analysis (including: Campylobacter, Salmonella, Shigella, Aeromonas, and E. coli). Analysis of the antral specimens showed no eosinophilic infiltrate. The duodenal specimens showed a severe mucosal lesion with marked but incomplete villous blunting, crypt hyperplasia, and severe chronic inflammation (Fig. 1). The colonic specimens showed severe inflammatory changes, erosion, regeneration, and focal cryptitis (Fig. 2). In a left colon specimen, rare inclusion bodies, characteristic of CMV infection, were found (Fig. 2). Additional CMV inclusions were seen in a second analysis. Routine CMV culture and CMV early antigen (CMV-EA) of the duodenal mucosa were positive. The CMV-EA was determined through immunofluorescence stain of the tissue cultured. Routine CMV culture and CMV-EA were negative in the colonic specimen. Immunohistochemical analysis of the colonic specimen showed CMV-infected cells. In Figure 3, a classic cytomegaloviral inclusion is seen after immunoperoxidase preparation. Urine CMV routine viral culture and CMV-EA were positive. Qualitative blood CMV-DNA was negative. Cytomegalovirus immunoglobulin (Ig) G was 1.11 ISR (normal, <0.9) and CMV IgM was less than 0.9 ISR (normal, <0.9). Both determinations were obtained by enzyme-linked immunosorbent assay (ELISA). At this point, after 25 days of intractable diarrhea with stool volume averaging 600 to 950 ml/day, intravenous ganciclovir at 10 mg/g per day was prescribed. Abruptly, after 2 days of ganciclovir, the stools became green and formed, and volume diminished to normal (13 ml/kg per day).FIG. 1: Duodenal mucosa. A severe mucosal lesion with marked but incomplete villous blunting and crypt hyperplasia was identified. There was marked chronic inflammation with a mild acute component. Original magnification, ×4; hematoxylin and eosin-stained, Bouin's-fixed specimen.FIG. 2: Colonic mucosa. Severe inflammatory changes, erosion, regeneration, and cryptitis were found. Within the epithelium and lamina propia enlarged cells with inclusions were present. Some had typical cytomegalovirus nuclear and cytoplasmic changes. The low-power microscopic view shows the mucosa injury; the high-power views (insets) demonstrate the inclusions. Original magnification, ×2; inset, ×60; hematoxylin and eosin-stained, Bouin's-fixed specimen.FIG. 3: Colonic mucosa. Immunohistochemical evidence of a typical cytomegaloviral inclusion (arrow). Original magnification, ×60. Three-step immunoperoxidase preparation using mouse anti-cytomegalovirus antibody, with horseradish peroxidase-conjugated rabbit anti-mouse antibody (Dako autostainer, Dako reagents, 3,3′-diaminobenzidine, tetrahydrochloride chromogen; Dako, Santa Barbara, CA, U.S.A.). Original magnification × 4; hematoxylin and eosin-stained, Bouin's-fixed specimen.The patient was treated for 14 days with intravenous ganciclovir, his feeding was advanced from one-quarter to full-strength elemental formula, and we observed that his absorption rapidly returned to normal. The patient's evaluation for human immunodeficiency virus was negative and B- and T-cell subsets were within normal limits (Table 1). Initial serum immunoglobulins were slightly decreased (IgG was subnormal), most likely because of protein-losing enteropathy secondary to mucosal injury. The last serum albumin (4.0 g/dl) and α1-antitrypsin in the stools were normal when he was 6 months of age, confirming resolution of protein-losing enteropathy. The last determination of serum immunoglobulins was within normal limits when the patient was 4 months of age. He had a head computed tomographic scan and a brain auditory-evoked potential test, both of which produced normal results. His most recent height was in the 95th percentile, and his weight was in the 75th percentile at 25 months of age. To date, he is symptom free and is consuming whole milk and a normal diet for his age. DISCUSSION Smith in 1956, Rowe et al. in 1956, and Weller et al. in 1957 independently isolated human CMV strains (20). After CMV was identified as a human pathogen, the diagnosis of infection was based on the demonstration of inclusion bodies in the affected tissue. Later, other methods such as culture and immunofluorescence stains were developed. More recently, polymerase chain reaction (PCR) has become a rapid test for detection of CMV infection in gastrointestinal tissue (17). In the past 2 decades more has been learned about CMV because of its pathogenic role in AIDS. Cases of CMV gastrointestinal infections have been seen only rarely in immunocompetent hosts (1,13,15,21,22). All these patients were adults, and some cases occurred before the description of AIDS in 1981 (15,22). Cytomegalovirus infection in patients without AIDS patients is more frequently localized in the upper gastrointestinal tract (13) in contrast to colonic involvement in AIDS patients (13,14). In comparison with cases of spontaneous CMV mononucleosis, these patients were older, usually had abdominal symptoms and rarely had lymphocytosis and atypical lymphocytes (1). Recently, in 1997 an immunocompetent infant was described with cow's milk allergy and CMV colitis. This patient had rectal bleeding that resolved by itself with feeding elemental formula and without antiviral therapy (23). Our patient had intractable diarrhea. He did not respond to the usual management, and the most common causes of diarrhea in infancy were ruled out. These conditions include standard colonic bacterial pathogens, Clostridium difficile, and viral pathogens, including rotavirus. Biopsy specimens obtained through endoscopy from the duodenum were positive for CMV culture. Even though the colonic specimens showed severe inflammatory changes, and CMV-infected cells were seen in a left colon specimen by routine staining with hematoxylin and eosin, CMV culture was negative. Colonic and rectal biopsy cultures have been shown to be positive in 50% to 80% of specimens with cytomegalic inclusion bodies (12,24). Most of these patients had variable degrees of inflammation with or without ulceration. In our case, specimens were obtained from normal-appearing mucosa, which decreases the sensitivity of the culture even further (17). Immunoperoxidase preparation from left colonic specimen confirmed the diagnosis. In some proven cases of gastrointestinal CMV infection, classic inclusions may be rare and difficult to detect, requiring great time and effort by the pathologist (4,6,16,17,21,25,26). Sometimes, inflammation causing tissue destruction can be so severe that CMV-inclusion bodies are difficult to recognize (13). There is evidence that specimens negative for CMV inclusion bodies by routine hematoxylin and eosin staining may be positive with immunoperoxidase staining for early and/or late viral antigens (27), immunohistologic examinations (28), or viral culture (7,8,12,16,29). Our patient had normal-appearing mucosa in the lower and upper gastrointestinal tracts, seen at endoscopy. Some studies have shown that the gastrointestinal mucosa may appear grossly normal or nonulcerated despite evidence of CMV infection in biopsy specimens (4,5,16). It has been postulated that the ischemia caused by cytomegaloviral vasculitis could be responsible for the pathogenesis of the necrotic ulcerations in the gastrointestinal tract (11,16,28). If the ulcers are absent in the gastrointestinal tract, it is because the endothelial cells have not been affected. In this case, viral invasion of the mucosal layer will explain the nonspecific inflammatory response (10) as it was seen in our patient (Figs. 1 and 2). Urine CMV viral culture was positive, supporting the diagnosis of CMV infection. However, isolation of CMV from urine must be interpreted with caution. Prolonged shedding of CMV in the urine may persist for months to years after infection and it may not necessarily represent current or recent infection (1,27,30). Cytomegalovirus DNA PCR from the blood was negative. Viremia may be negative in patients with histologically determined CMV disease, because viremia can be intermittent (3). After 25 days of intractable diarrhea, the patient dramatically improved 48 hours after a regimen of intravenous ganciclovir was begun. By day 2 of therapy he had normal stools. This outcome has been reported before, with favorable response seen in approximately 80% of immunocompromised patients with CMV gastrointestinal disease, regardless of the underlying cause of immunosuppression (31). Signs of CMV disease developed in our previously healthy patient when he was 7 weeks of age. It is not clear how he acquired the disease. Cytomegalovirus IgM was negative, whereas CMV IgG was positive, presumably because of transplacental transfer, which makes vertical transmission possible. Cytomegalovirus IgM is usually positive by 3 to 4 weeks of life in congenital infection and remains elevated for weeks to months (32). In perinatal and postnatal CMV infection CMV IgM becomes positive at 8 to 18 weeks of age, depending on the time of exposure (32,33). One possibility is that the CMV IgM was evaluated in our patient in the period between viral exposure and antibody production. Another possibility is that CMV IgM was falsely negative, because ELISA determination of CMV IgM has a 70% sensitivity. For this reason, a clinician should not rely solely on ELISA to diagnose CMV infection (34). Unfortunately, we were not allowed by his parents to repeat CMV titers. The total CMV antibody was positive in his mother (IgG and IgM titers were not available). In addition, a postnatal transmission through breast milk is possible. In one series, it was reported that 58% of newborns exposed to CMV through breast milk are infected; however, morbidity was minimal (35). Overall, 5% to 7% of CMV-infected infants at birth are symptomatic (34). Overall, 30% of seropositive mothers excrete CMV into breast milk during postpartum months 2 through 4 (33), the time during which our patient showed evidence of CMV infection. This is the first case reported of CMV enterocolitis in an immunocompetent infant host who had intractable diarrhea that was successfully treated. Previously, CMV has not been recognized as a cause of this disorder. A reasonable index of suspicion for diagnosis of CMV enterocolitis should be maintained in any infant who has prolonged and severe diarrhea that is negative for the most common causes in infancy and that does not respond to standard management. In this setting, endoscopy is indicated, and specimens obtained should be subjected to CMV culture; immunohistologic testing for CMV; and, if possible, PCR analysis, because inclusion bodies may be difficult to find, as has been shown in previous reports. This leads to the establishment of appropriate and specific therapy avoiding the self-perpetuating cycle and prolonged total parenteral nutrition often needed in intractable diarrhea. As our ability to establish specific diagnosis improves, we may reach the point at which the category of undetermined diagnoses in intractable diarrhea will disappear. Acknowledgment: The authors thank Dr. Paul Krogstad, Division of Pediatric Infectious Diseases, University of California Los Angeles Medical Center, for review of the manuscript and helpful comments." @default.
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• W2328837568 title "Cytomegalovirus Enterocolitis in an Immunocompetent Infant Host: Another Cause of Treatable Intractable Diarrhea in Infancy" @default.
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